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topotecan

( toe-poe-TEE-can )
Funding:
New Drug Funding Program
  • Topotecan - Single Agent Treatment of Platinum Sensitive Ovarian Fallopian Tube or Primary Peritoneal Cancer
  • Topotecan - Platinum-Resistant Ovarian Fallopian Tube or Primary Peritoneal Cancer
Other Name(s): Hycamtin® (multiple brands available)
Appearance: Clear, colourless solution mixed into larger bags of fluids
A - Drug Name

topotecan

SYNONYM(S):   hycamptamine; SKF 104864

COMMON TRADE NAME(S):   Hycamtin® (multiple brands available)

 
B - Mechanism of Action and Pharmacokinetics

Topotecan is a semi-synthetic analogue of camptothecin, an agent derived from the Oriental yew tree, Camptotheca accuminata. The cytotoxic effects of the camptothecins are believed to be related to their activity as inhibitors of topoisomerase – I, an enzyme involved in the replication and repair of nuclear DNA. As DNA is replicated in dividing cells, topoisomerase-I acts by binding to super-coiled DNA and causing single-stranded breaks in that DNA. As a result, topoisomerase –I is able to relieve the torsional stresses that are introduced into DNA ahead of the replication complex or moving replication fork. Topotecan binds to the DNA and the topoisomerase complex and prevents religation of DNA strand breaks, leading to cell death.



Absorption
Oral: 42 %
Distribution

Topotecan is evenly distributed between blood cells and plasma. Pharmacokinetics are dose proportional.

Cross blood brain barrier? Yes
PPB 35 %
Metabolism

Topotecan undergoes pH-dependent hydrolysis at pH of 4 or less to create an active lactone form, with the equilibrium favouring the ring-opened hydroxyacid form at physiologic pH. It is also metabolized in the liver to N-desmethyl topotecan.

Active metabolites Lactone form, n-desmethyl metabolite
Inactive metabolites Hydroxyacid form, n-desmethyl metabolite, glucuronides
Elimination

Topotecan is eliminated primarily in the urine with some elimination via the biliary route.

Urine 51% unchanged within 9 days, along with some metabolites
Half-life (terminal) : 2-3 hours (IV)
 
C - Indications and Status
Health Canada Approvals:

  • For the treatment of metastatic cancer of the ovary after failure of initial or subsequent therapy
  • For the treatment of sensitive (relapsed ≥ 60 days after first-line chemotherapy) small cell lung cancer after failure of first-line chemotherapy


Other Uses:

  • Cervical cancer
  • Ewing's sarcoma
  • Soft tissue sarcoma
 
D - Adverse Effects

Emetogenic Potential:  

Low

Extravasation Potential:   Minimal

ORGAN SITE SIDE EFFECT* (%) ONSET**
Dermatological Alopecia (49%) E
Rash (16%) (may be severe) I  E
Gastrointestinal Abdominal pain (22%) E
Anorexia (19%) I
Constipation (29%) E
Diarrhea (32%) E
GI obstruction (5%) (reported in ovarian cancer patients) E
Mucositis (18%) E
Nausea, vomiting (64%) I
Typhlitis (rare) E
General Fatigue (29%) E
Pain (23%) E
Hematological Myelosuppression ± infection, bleeding (grade 4: 78%) E
Hepatobiliary ↑ LFTs (8%) (2% severe) E
Hypersensitivity Hypersensitivity I
Musculoskeletal Muscle weakness (5%) E
Musculoskeletal pain (5%) E
Nervous System Headache (18%) E
Paresthesia (7%) E
Respiratory Cough, dyspnea (22%) I  E
Pneumonitis (rare) E  D


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for topotecan include nausea, vomiting, alopecia, diarrhea, constipation, fatigue, pain, abdominal pain, cough, dyspnea, anorexia and headache.

Prophylactic use of antiemetics was not routine in patients treated with topotecan.

Myelosuppression is the dose-limiting toxicity of topotecan, particularly neutropenia, which occurs more frequently and is often more severe than thrombocytopenia. It is dose-related, reversible and non-cumulative, but complicated by infection or fever in 23% of patients and 7% of cycles. Neutropenia is more severe in heavily pre-treated patients. Decreased renal function is associated with a lower MTD and more marked neutropenia. Neutropenic colitis (typhlitis/caecitis) have been reported in clinical trials.

For patients who present with cough, fever, dyspnea and/or hypoxia suggestive of interstitial lung disease (ILD), treatment should be interrupted and patients should be managed accordingly. If ILD is diagnosed, topotecan should be discontinued.

Most of the non-hematologic toxicities are mild to moderate in severity and not dose-limiting.

 
E - Dosing

Refer to protocol by which patient is being treated. Numerous dosing schedules exist depending on disease, response and concomitant therapy; doses may be lower for combination regimens.  Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.



Adults:

Prior to administration of the first course of topotecan, patients must have a baseline neutrophil count of ≥ 1.5 x 109/L, a platelet count of > 100 x 109/L, and a hemoglobin level of ≥90 g/L.


Intravenous: 1.5 mg/m² over 30 minutes Days 1 to 5 every 3 weeks

Dosage with Toxicity:

Dose levels: 1.5 mg/m2, 1.25 mg/m2, 1 mg/m2

 

Worst Toxicity Previous Cycle

Action1
 

Grade 4 neutropenia ≥ 7 days

 
 

Reduce dose by 1 dose level

OR

Use G-CSF with next cycle

Febrile neutropenia

 

Cycle delay for hematologic toxicity

 
Platelets  <25 x 109/L
 

Reduce dose by  1 dose level

Reduce dose by  1 dose level

Grade 3 GI or organ toxicity

Symptoms suggestive of pneumonitis

Hold and manage patient appropriately. Discontinue if confirmed.

Grade 4 GI or organ toxicity

 

Discontinue
1. Do not retreat until neutrophils ≥ 1 x 109/L,  platelets ≥ 100 x 109/L, hemoglobin ≥90 g/L (after transfusion if necessary) and other toxicity ≤ grade 2.


Dosage with Hepatic Impairment:

No dosage adjustment is required for treating patients with bilirubin < 171 μmol/L. Total topotecan clearance in patients with hepatic impairment only decreased by about 10%, as compared to the control group of patients.



Dosage with Renal Impairment:

Creatinine Clearance (mL/min)  Adjusted dose
40-60 no change
  20-39   0.75mg/m2
    <20      contraindicated


Dosage in the elderly:

No dosage adjustment needed other than for renal function as above.



Children:

Safety and efficacy have not been established.



 
F - Administration Guidelines

  • Mix in 50mL-100mL minibag (NS or D5W); infuse over 30 minutes.
  • Final concentration should be between 0.02 mg/mL to 0.5 mg/mL.


 
G - Special Precautions
Contraindications:

  • Patients with hypersensitivity to topotecan or any of its excipients
  • Patients with pre-existing severe myelosuppression
  • Patients with severe renal impairment (CrCl <20 mL/min)

Other Warnings/Precautions:

  • Use with caution in patients with risk factors for pneumonitis


Other Drug Properties:

  • Carcinogenicity: Unknown

Pregnancy and Lactation:
  • Genotoxicity: Yes
  • Mutagenicity: Yes
  • Fetotoxicity: Yes
  • Teratogenicity: Yes

    Topotecan is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.

     

  • Excretion into breast milk: Yes

    Breastfeeding is not recommended.

 
H - Interactions

In vitro, topotecan did not inhibit CYP1A2, 2A6, 2C8/9, 2C19, 2D6, 2E, 3A or 4A.

AGENT EFFECT MECHANISM MANAGEMENT
Cisplatin when given on day 1 ↑ Severity of myelosuppression Additive Avoid or reduce doses of cisplatin and topotecan
G-CSF (concomitant) Prolong duration of neutropenia If G-CSF is to be used, it should not be initiated until day 6 of the course of therapy.
Curcumin (Tumeric) May reduce effect of topotecan Inhibits topotecan induced apoptosis Avoid concomitant use
Phenytoin ↓ effect of topotecan ↑ clearance of Topotecan, due to possible ↑ in metabolism Avoid or may need to increase topotecan dose
Docetaxel when given on day 4 of topotecan treatment 50% decrease in docetaxel clearance Topotecan may change docetaxel metabolism by CYP3A4 inhibition Give docetaxel on day 1 of topotecan treatment
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline and before each cycle

Liver and renal function tests

Baseline and at each visit

Clinical toxicity assessment of GI, skin, infection, bleeding and pulmonary effects.

At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
J - Supplementary Public Funding

New Drug Funding Program (NDFP Website )

  • Topotecan - Single Agent Treatment of Platinum Sensitive Ovarian Fallopian Tube or Primary Peritoneal Cancer
  • Topotecan - Platinum-Resistant Ovarian Fallopian Tube or Primary Peritoneal Cancer

 
K - References

Herben VM, Rosing H, ten Bokkel Huinink WW et al. Oral topotecan: bioavailability and effect of food co-administration. Br J Cancer 1999;80(9):1380-6.

McEvoy GK, editor. AHFS Drug Information 2011. Bethesda: American Society of Health-System Pharmacists, p. 1245-8.

Ormrod D, Spencer CM. Topotecan a review of its efficacy in small cell lung cancer. Drugs 1999;58 (3):533-51.

Product Monograph: Hycamtin® (topotecan). GlaxoSmithKline Inc., July 9, 2009.

Summary of Product Characteristics:  Hycamtin® (topotecan). SmithKline Beecham (UK), October 28, 2010.

Somasundaram S, Edmund NA, Moore DT, et al. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 2002;62(13):3868-75.

Zamboni WC, Gajjar AJ, Heideman RL, et al. Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma. Clin Cancer Res 1998;4(3):783-9.

Zamboni WFC, Egorin MJ, Van Echo DA, et al. Pharmacokinetic and pharmacodynamic study of the combination of docetaxel and topotecan in patients with solid tumors. J Clin Oncol 2000;18:3288-94.


November 2017 updated public funding (removed archived forms)

 
L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

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